This invention generally relates to pharmaceuticals and more specifically to a method and compositions for inducing penile erections in human males suffering from impotence, a method and compositions for treating female sexual dysfunction, and a method and compositions for treating human anal disease resulting from excessive anal sphincter tone.
Male erectile dysfunction is a widespread disorder that is thought to affect about ten to fifteen percent of the adult men. In a similar fashion, it is now beginning to be recognized that female sexual dysfunction is also a significant problem among adult women. With the male cases, a number of causes of these insufficiencies, in addition to anatomical deficiencies of the penis that preclude an erection sufficient for vaginal penetration, have been identified. Causes of erectile dysfunction can be categorized as psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and in any male suffering from erectile dysfunction there may be more than one cause. Female sexual dysfunction may also be categorized as psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and a female with one or more of these etiologies may also experience a lack of satisfaction in sexual relations.
Psychogenic impotence is often the result of anxiety or depression, with no apparent somatic or organic impairment. Neurogenic impotence may arise from, for example, surgery or a pelvic injury, involving the nervous system affecting the penis or vagina. Sexual dysfunction which is in endocrinologic in origin is most often associated with the disorders hypo- or hypergonadotropic hypogonadism and hyperprolactinein the male and decreases in estrogens in the female.
Vasculogenic sexual dysfunction is thought to be the most frequent cause of sexual dysfunction accounting for approximately fifty percent of all cases of organic sexual dysfunction. In these cases, the erectile dysfunction may be attributed to alterations in the flow of blood to and from the penis while in the female cases vaginal engorgement insufficiency and clitoral erectile insufficiency may be attributed to alterations in blood flow to the vagina and clitoris respectively. Atherosclerotic or traumatic arterial occlusive disease to the arteries which supply blood to the penis can lead to a decrease in the rigidity of the erect penis as well as increase the time to achieving maximal erection. In an analogous fashion, disease which impairs blood flow to the hypogastric-vaginal/clitoral arterial bed may lead to vaginal engorgement insufficiency and clitoral erectile insufficiency. In still other cases, there is an inability to retain blood in the penis or clitoris such that sufficient pressure for an erection can be neither obtained nor maintained.
There is also a high incidence of erectile insufficiency among male diabetics, particularly those with insulin-dependent diabetes mellitus. Erectile dysfunction in male diabetics is often classified as xe2x80x9cdiabetogenic,xe2x80x9d although the underlying dysfunction is usually neurogenic and/or vasculogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics. A significant population of female diabetics also exhibit symptoms of sexual dysfunction, especially those with complications directly attributed to the disease.
Sexual dysfunction in both males and females is sometimes a side effect of certain drugs, such as beta-antagonists that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to sexual dysfunction. These forms of sexual dysfunction may be regarded as iatrogenic sexual dysfunction.
A number of methods to treat sexual dysfunction are available. These treatments include pharmacological treatments, surgery and, in cases of psychogenic dysfunction, psychological counseling is sometimes effective. Psychogenic sexual dysfunction often can be cured by counseling. Insufficiency due to excessive alcohol consumption is sometimes cured by reducing or eliminating such consumption.
In the rare cases in males, where the insufficiency is untreatable because of venous leakage, surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency amenable to treatment by pharmacological methods. Also, penile implants, which provide a mechanic means to produce an erection sufficient for vaginal penetration, are widely used to treat impotence. In recent years, implants have been employed, especially in cases where pharmacological intervention is ineffective. Such cases are usually associated with severe forms of vasculogenic impotence. Treatment of impotence with penile implants, however, entails serious disadvantages. Such treatment requires surgery and necessitates total destruction of the erectile tissues of the penis, forever precluding normal erection.
In the male population, pharmacological methods of treatment are also available. Such methods, however, have not proven to be highly satisfactory or without potentially severe side-effects. Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved. Injection of papaverine, a phosphodiesterase inhibitor and a smooth muscle relaxant, or phenoxybenzamine, a non-specific xcex1-adrenergic antagonist and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration however, these treatments are not without the serious and often painful side effect of priapisim. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an xcex1-adrenergic antagonist, has been shown to produce an erection sufficient for vaginal penetration, however, the resulting erection is one of significantly shorter duration than that induced by intracavernosal injection of papaverine or phenoxybenzamine. Thus, often times the erection is of such short duration that satisfactory sexual relations are difficult or impossible. As an alternative or, in some cases an adjunct to phosphodiesterase inhibition or xcex1-adrenergic blockade for the treatment of erectile dysfunction, prostaglandin E1 (PGE1) has been administered via intracavernosal injection. A major side effect frequently associated intracorprally delivered PGE1 is penile pain and burning. Thus, there is a need for methods to induce and maintain a penile erection for a sufficient duration that satisfactory sexual relations are possible without also producing the undesirable side effects of those agents currently used. With regard to female sexual dysfunction, no pharmacological strategies have been yet devised for effective treatment
A number of anorectal diseases involve excessive anal sphincter tone. For example, anal fissures as well as acutely thrombosed external hemorrhoids are normally accompanied by severe anal pain. Classical treatment of these conditions has usually involved surgery, however, in the treatment of more severe cases, surgical intervention is not without adverse side effects usually involving permanent sphincter defects and subsequent continence disturbances. Recently, nitric oxide has been implicated as the chemical messenger mediating relaxation of the internal anal sphincter. The local application of the exogenous nitric oxide (NO) donors nitroglycerin or isosorbide dinitrate has been reported to improve the symptoms and, in the case of anal fissure, facilitate the healing process. These treatments have not been without the production of undesired systemic side effects the most prevalent of which is headache. Thus, there is a need for methods to treat human anal disease involving excessive anal sphincter tone without also producing the undesirable side effects of those agents currently used.
Nitric oxide has been shown to mediate a number of actions including the bactericidal and tumoricidal actions of macrophages and blood vessel relaxation of endothelial cells. NO, and NO donors have also been implicated as mediators of nonvascular smooth muscle relaxation. This effect includes the dilation of the corpus cavernosum smooth muscle, an event involved in the penile and clitoral erection processes and the relaxation of the anal sphincter, an event necessary for normal defecation as well as an improvement in the symptoms of pain associated with many anal diseases. However, the effects of modified of phosphodiesterase inhibitors which are directly or indirectly linked with a nitric oxide adduct have not been investigated.
In the process of arriving at the present invention it was recognized that the risk of toxicities and adverse effects that are associated with high doses of phosphodiesterase inhibitors can be avoided by the use of such phosphodiesterase inhibitors when nitrosated or nitrosylated. Such toxicities and adverse effects include hypotension, syncope, as well as priapism. The smooth muscle relaxant properties of phosphodiesterase inhibitors and of compounds that donate, release or transfer nitrogen monoxide work together to permit the same efficacy with lower doses of the phosphodiesterase inhibitors.
Accordingly, in one aspect the invention provides novel nitrosated and nitrosylated phosphodiesrase inhibitors (NOn-PDE inhibitor) wherein n is 1 or 2. The phosphodiesterase inhibitor can be nitrosylated or nitrosated through sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
In another aspect the invention provides a composition comprising a therapeutically effective amount of an phosphodiesterase inhibitor (PDE inhibitor), which can optionally be substituted with at least one NO or NO2 moiety, and one to ten fold molar excess of a compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NO.). The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
In another aspect, the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor.
In another aspect, the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or NO2 moiety, and a compound that donates. transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NO.). The PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO2 group, and nitric oxide donor can be administered separately or as components of the same composition.
In another aspect, the invention provides a method for treating female sexual dysfunction in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor.
In another aspect, the invention provides a method for treating treating female sexual dysfunction in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or NO2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NO.). The PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO2 group, and nitric oxide donor can be administered separately or as components of the same composition.
In another aspect, the invention provides a method for treating anal disease resulting from excessive anal sphincter tone in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor.
In another aspect, the invention provides a method for treating treating anal disease resulting from excessive anal sphincter tone in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an PDE inhibitor which can optionally be substituted with at least one NO or NO2 moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NO.). The PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one NO or NO2 group, and nitric oxide donor can be administered separately or as components of the same composition.
The nitrosated or nitrosylated PDE inhibitor and the compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of NO or EDRF in vivo can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
The following drawings are illustrative of embodiments of the invention and do not limit the scope of the invention as defined by the claims.
The term xe2x80x9clower alkylxe2x80x9d as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to R50Oxe2x80x94 wherein R50 is lower alkyl as defined in this specification. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term xe2x80x9chydroxyxe2x80x9d as used herein refers to xe2x80x94OH.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a hydroxy group as previously defined appended to a lower alkyl group as previously defined.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a branched or straight chain C2-C10 hydrocarbon which also comprises one or more carbon-carbon double bonds.
The term xe2x80x9caminoxe2x80x9d as used herein refers to xe2x80x94NH2.
The term xe2x80x9cnitratexe2x80x9d as used herein refers to xe2x80x94Oxe2x80x94NO2.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to R50NHxe2x80x94 wherein R50 is as defined in this specification, for example, methylamino, ethylamino, butylamino, and the like.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to R52R53Nxe2x80x94 wherein R52 and R53 are independently selected from lower alkyl groups as defined in this specification, for example dimethylamino, diethylamino, methyl propylamino and the like.
The term xe2x80x9cnitroxe2x80x9d as used herein refers to the group xe2x80x94NO2 and xe2x80x9cnitrosatedxe2x80x9d refers to compounds that have been substituted therewith.
The term xe2x80x9cnitrosoxe2x80x9d as used herein refers to the group xe2x80x94NO and xe2x80x9cnitrosylatedxe2x80x9d refers to compounds that have been substituted therewith.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9calkylarylxe2x80x9d as used herein refers to a lower alkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to an alkoxy radical to which is appended an aryl group. Representative arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9cbridged cycloalkylxe2x80x9d herein refers to two or more cycloalkyl radicals fused via adjacent or non-adjacent carbon atoms, including but not limited to adamantyl and decahydronapthyl.
The term xe2x80x9ccycloalkoxyxe2x80x9d as used herein refers to R54Oxe2x80x94 wherein R54 is cycloalkyl as defined in this specification. Representative examples of alkoxy groups include cyclopropoxy, cyclopentyloxy, and cyclohexyloxy and the like.
The term xe2x80x9carylthioxe2x80x9d herein refers to R55Sxe2x80x94 wherein R55 is an aryl group.
The term xe2x80x9calkylsulfinylxe2x80x9d herein refers to R50xe2x80x94S(O)2xe2x80x94 wherein R50 is as defined in this specification.
The term xe2x80x9ccarboxamidoxe2x80x9d herein refers to xe2x80x94C(O)NH2.
The term xe2x80x9ccarbamoylxe2x80x9d herein refers to xe2x80x94Oxe2x80x94C (O)NH2.
The term xe2x80x9ccarboxylxe2x80x9d herein refers to xe2x80x94CO2H.
The term xe2x80x9ccarbonylxe2x80x9d herein refers to xe2x80x94C(O)xe2x80x94.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein refers to I, Br, Cl, or F.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical to which is appended one or more halogens. Representative examples of a haloalkyl group include trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2 chloro-pentyl and the like.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to a haloalkyl radical to which is appended an alkoxy group. Representative examples of haloalkoxy groups include, 1,1,1-trichloroethoxy, 2-bromobutoxy and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein refers to a mono- or bi- cyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups (including bicyclic heteroaryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro. Examples of heteroaryl groups include but are not limited to pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, thiazole, isothiazole, benzothiazole, benzoxazole, thiadiazole, oxazole, pyrrole, imidazole and isoxazole.
The term xe2x80x9cheterocyclic ringxe2x80x9d refers to any 3-, 4-, 5-, 6-, or 7-membered nonaromatic ring containing at leas one nitrogen atom, oxygen, or sulfur atom which is bonded to an atom which is not part of the heterocyclic ring.
The term xe2x80x9carylheterocyclic ringxe2x80x9d as used herein refers to a bi- or tricyclic ring comprised of an aryl ring as previously defined appended via two adjacent carbons of the aryl group to a heterocyclic ring as previously defined.
The term xe2x80x9cheterocyclic compoundsxe2x80x9d herein refers to mono and polycyclic compounds containing at least one heteroaryl or heterocyclic ring.
The term xe2x80x9camidoxe2x80x9d as used herein refers to xe2x80x94NHxe2x80x94C(O)xe2x80x94R56 wherein R56 is a lower akyl, aryl, or hereroaryl group as defined in this specification
The term xe2x80x9calkylamidoxe2x80x9d as used herein refers to R50Nxe2x80x94C(O)xe2x80x94R56 wherein R50 is as defined in this specification and R56 is a lower akyl, aryl, or hereroaryl group as defined in this specification.
Examples of contemplated PDE inhibitors to which a nitric oxide adduct may be directly or indirectly linked include dipyridamole, zaprinast, sildenafil, filaminast, denbufyllene, piclamilast, zardaverine, rolipram, papaveroline, E4021, and triflusal.
Sources of information for the above include Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc., 1996; the Physician""s Desk Reference (49th Ed.), Medical Economics (1995); Drug Facts and Comparisons (1993 Ed), Facts and Comparisons (1993); and The Merck Index (12th Ed.), Merck and Co., Inc. (1996), all of which are incorporated herein by reference in their entirety.
A principal aspect of the invention relates to novel nitrosated and/or nitrosylated phosphodiesterase inhibitors.
One embodiment of this aspect provides compounds having the structure: 
wherein,
R1 is alkoxy, cycloalkoxy, halogen, or 
R2 is hydrogen, alkoxy, or haloalkoxy; and
R3 is selected from: 
xe2x80x83wherein
D is selected from (i) xe2x80x94NO; (ii) xe2x80x94NO2; (iii) xe2x80x94C(Rd)xe2x80x94Oxe2x80x94C(O)xe2x80x94Yxe2x80x94Zxe2x80x94[C(Re)(Rf)]pxe2x80x94Txe2x80x94Q in which Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or Ni in which Ri is hydrogen, lower alkyl, Re and Rf at each occurrence are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, amino, alkylamino, amido, alkylamido, dialkylamino, carboxy, or taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6, T is a covalent bond, oxygen, sulfur or nitrogen, Z is selected from a covalent bond, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or arylheterocyclic ring, and Q is selected from xe2x80x94NO or xe2x80x94NO2; (iv) xe2x80x94C(O)xe2x80x94T1xe2x80x94Zxe2x80x94[C(Re)Rf)]pxe2x80x94T2xe2x80x94Q wherein T1 and T2 are independently selected from T and Re, Rf, p, Q, Z, and T are as defined in this specification; (v) xe2x80x94C(O)xe2x80x94Zxe2x80x94[Gxe2x80x94[C(Re)(Rf)]pxe2x80x94Txe2x80x94Q]p wherein G is (i) a covalent bond; (ii)xe2x80x94Txe2x80x94C(O)xe2x80x94; (iii) xe2x80x94C(O)xe2x80x94T, or (iv) Y, and wherein Re, Rf, p, Q, T, Y, and Z are as defined in this specification; (v) xe2x80x94C(O)xe2x80x94T[C(Ry)(Rz)]p wherein Ry and Rz are independently selected from xe2x80x94T1xe2x80x94[C(Re)(Rf)]pxe2x80x94Gxe2x80x94[C(Re)(Rf)]pxe2x80x94T2xe2x80x94 wherein G, Re, Rf, p, Q, T, T1, and T2 are as defined in this specification;
R4 is selected from (i) hydrogen, (ii) xe2x80x94C(Rd)xe2x80x94Oxe2x80x94C(O)xe2x80x94Yxe2x80x94Zxe2x80x94[C(R)(Re)(Rf)]pxe2x80x94Txe2x80x94Q, (iii) xe2x80x94C(O)xe2x80x94T1xe2x80x94[C(Re)(Rf)]pxe2x80x94T2xe2x80x94Q, (iv) xe2x80x94C(O)xe2x80x94Zxe2x80x94[Gxe2x80x94[C(Re)(Rf)]pxe2x80x94Txe2x80x94Q]p; and wherein Rd, Re, Rf, p, G, T1, T2, Q, Y, and Z are defined as in this specification;
R5 is selected from a lone pair of electrons or xe2x80x94C(Rd)xe2x80x94Oxe2x80x94C(O)xe2x80x94Yxe2x80x94Zxe2x80x94[C(Re)(Rf)]pxe2x80x94Txe2x80x94Q wherein Rd, Re, Rf, p, T, T1, T2, Q, Y, and Z are defined as in this specification;
R11 and R12 are independently selected from hydrogen or R4 wherein R4 is as defined in this specification with the provision that R11 and R12 are not both hydrogen;
X is a halogen and;
D1 is selected from D or hydrogen and wherein D is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R4 is as defined in this specification;
R8 is selected from hydrogen or lower alkyl;
R9 is selected from hydrogen or halogen; and
R10 is selected from:
(i) hydrogen 
wherein R8 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
E is selected from nitrogen or xe2x80x94CHxe2x80x94;
G is selected from nitrogen or xe2x80x94C(R8)xe2x80x94;
R21 is selected from: 
R22 is selected from R12 or lower alkyl; and
R8, R11, and R12 are as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
F is selected from xe2x80x94CH2xe2x80x94 or sulfur;
R4 and Ra are as defined in this specification; and
R13 is selected from: 
xe2x80x83wherein,
R6 and R7 are independently selected from hydrogen or R4 wherein R4 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R4 is as defined in this specification; and
R14 is selected from: 
wherein R6 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R15 is hydrogen, lower alkyl, R4, or xe2x80x94(CH2)4xe2x80x94C(CH3)2xe2x80x94Oxe2x80x94D1;
R16 is lower alkyl; and
R17 is hydrogen, lower alkyl, CH3xe2x80x94C(O)xe2x80x94CH2xe2x80x94, CH3xe2x80x94Oxe2x80x94CH2xe2x80x94, or D with the provision that either R15 or R17 must be selected to contain D and wherein D and D1 are as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R4 and R8 are as defined in this specification and
R18 is selected from: 
and wherein R8 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R19 is selected from: 
and wherein R4, R11, and R12 are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R20 is selected from: 
and wherein R4 is defined as in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
a is an integer from 2 to 3 and D and D1 are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein D and D1 are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
J is selected from: 
K is selected from: 
wherein V is carbon or nitrogen;
R23, R24, R25, R26, R27, R28, R29, and R30 are independently selected from hydrogen, halogen, alkoxy, nitrile, carboxamido, or carboxyl; and wherein p, Re, Rf, T, T1, T2, Y and D are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure: 
wherein,
R31 is alkyl, halogen, haloalkyl, or haloalkoxy;
R32 is selected from D1 or xe2x80x94C(O)R8; and
wherein D1 and R8 are defined as in this specification.
Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof.
Another aspect of the invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes.
Some of the compounds of the invention are synthesized as shown in FIGS. 1 through 39 presented below, in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, Re, Rf, p, D, D1, E, F, G, J, K, and X are as defined i n this specification or as depicted in the reaction schemes for structures I-XIII; P1 is an oxygen protecting group and P2is a sulfur protecting group. The reactions are performed in solvents appropriate to the reagents and materials employed are suitable for the transformations being effected. It is understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art. The use of sulfur and oxygen protecting groups is well known in the art for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c.f., T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, New York (1991).
Another embodiment of this aspect provides processes for making compounds having structures I and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (I) wherein R1, R2, Re, Rf, and p are defined as in this specification and a nitrite containing imide is representative of the R3 group as defined in this specification may be prepared as outlined in FIG. 1. The amide group of formula 1 is converted to the imide of formula 2 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IA.
Nitroso compounds of formula (I) wherein R1, R2, Re, Rf, and p are defined as in this specification and a nitrosothiol containing imide is representative of the R3 group as defined in this specification may be prepared as outlined in FIG. 2. The amide group of formula 1 is converted to the imide of formula 3 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IB. Alternatively, treatment of the deprotected thiol derived from compound 3 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula IB.
Nitro compounds of formula (I) wherein R1, R2, Re, Rf, and p are defined as in this specification and an nitrate containing imide is representative of the R3 group as defined in this specification may be prepared as outlined in FIG. 3. The amide group of the formula 1 is converted to the imide of the formula 4 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred halides are bromide and iodide. Reaction of the imide of the formula 4 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IC.
Another embodiment of this aspect provides processes for making compounds having structures II and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (II) wherein R8, R9, R10, Re, Rf, and p are defined as in this specification, and a nitrite containing amide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 4. The imidazo[2,1-b]quinazoline of formula 5 is converted to the acylimidazo[2,1-b]quinazoline of formula 6 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of acylimidazo[2,1-b]quinazolines are reacting the imidazo[2,1-b]quinazoline with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the imidazo[2,1-b]quinazoline and protected alcohol containing acid in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3 (3dimethylaminopropyl) carbodimide hydrochloride (EDAC. HCl) with or without a catalyst such as 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt). Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIA.
Nitroso compounds of formula (II) wherein R8, R9, R10, Re, Rf, and p are defined as in this specification, and a nitrosothiol containing amide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 5. The imidazo[2,1-b]quinazoline of formula 5 is converted to the acylimidazo[2,1-b]quinazoline of formula 7 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of acylated imidazo[2,1-b]quinazolines are reacting the imidazo[2,1-b]quinazoline with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the imidazo[2,1-b]quinazoline and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with or without a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIB. Alternatively, treatment of the deprotected thiol derived from compound 7 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula IIB.
Nitro compounds of formula (II) wherein R8, R9, R10, Re, Rf, and p are defined as in this specification, and a nitrate containing amide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 6. The imidazo[2,1-b]quinazoline of formula 5 is converted to the acylimidazo[2,1-b]quinazoline of formula 8 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of the acylimidazo[2,1-b]quinazolines are reacting the imidazo[2,1-b)quinazoline with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with or without a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the acylimidazo[2,1-b]quinazoline of the formula 8 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IIC.
Another embodiment of this aspect provides processes for making compounds having structures III and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (III) wherein E, G, R21, R22, Re, Rf, and p are defined as in this specification and a nitrite containing amide is representative of the R11 group as defined in this specification may be prepared as outlined in FIG. 7. The purine-6-one group of formula 9 is converted to the acylated purine6-one of formula 10 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of acylated purine-6-ones are reacting the purine-6-one with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIA.
Nitroso compounds of formula (III) wherein E, G, R21, R22, Re, Rf, and p are defined as in this specification and an nitrosothiol containing amide is representative of the R11 group as defined in this specification may be prepared as outlined in FIG. 8. The purine group of formula 9 is converted to the acylated purine-6-one of formula 11 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of acylated purine4-ones are reacting the purine-6-one with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIIB. Alternatively, treatment of the deprotected thiol derived from compound 11 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula IIIB.
Nitro compounds of formula (III) wherein E, G, R21, R22, Re, Rf, and p are defined as in this specification and an nitrate containing amide is representative of the R11 group as defined in this specification may be prepared as outlined in FIG. 9. The purine4-one of formula 9 is converted to the acylated purine6-one the of formula 12 wherein p, Re and Rf are defined and X is halogen. Preferred methods for the formation of acylated purine6-ones are reacting the purine one with the preformed acid chloride or symmetrical anhydride of the halide containing acid. Preferred halides are bromide and iodide. Reaction of the of the acylated purine4one of the formula 12 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IIIC.
Another embodiment of this aspect provides processes for making compounds having structures IV and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (IV) wherein F, R8, R13, Re, Rf, and p are defined as in this specification and a nitrite containing acyl hydrazide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 10. The 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine of formula 13 is converted to the 3 (2-acyl)-pyridazinone or 2-acyl-1, 2, 3, 4-thiadiazine of formula 14 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of 3 (2-acyl)-pyridazinone or 2-acyl-1, 2, 3, 4-thiadiazine are reacting the 3 (2H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine and protected alcohol containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IVA.
Nitroso compounds of formula (IV) wherein F, R8, R13, Re, Rf, and p are defined as in this specification and a nitrosothiol containing acyl hydrazide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 11. The 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine of formula 13 is converted to the 3 (2-acyl)-pyridazinone or 2-acyl-1, 2, 3, 4-thiadiazine of formula 15 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of 3 (2-acyl)-pyridazinones or 2-acyl-1, 2, 3, 4-thiadiazines are reacting the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IVB. Alternatively, treatment of the deprotected thiol derived from compound 15 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula IVB.
Nitro compounds of formula (IV) wherein F, R8, R13, Re, Rf, and p are defined as in this specification and an nitrate-containing acyl hydrazide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 12. The 3 (2-H) pyridazinone or 2H-1, 2, 3, 4thiadiazine of formula 13 is converted to the 3 (2-acyl)pyridazinone or 2-acyl-1, 2, 3, 4-thiadiazine of formula 16 wherein p, Re and Rf are defined and X is halogen. Preferred methods for the formation of 3 (2-acyl)-pyridazinones or 2-acyl-1, 2, 3, 4-thiadiazines are reacting the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the 3 (2-H)-pyridazinone or 2H-1, 2, 3, 4-thiadiazine and halide containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the 3 (2-acyl)-pyridazinone or 2-acyl-1, 2, 3, 4-thiadiazine of formula 16 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IVC.
Another embodiment of this aspect provides processes for making compounds having structures V and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (V) wherein R14, Re, Rf, and p are defined as in this specification and an nitrite containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 13. The amide group of formula 17 is converted to the imide of formula 18 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VA.
Nitroso compounds of formula (V) wherein R14, Re, Rf, and p are defined as in this specification and a nitrosothiol containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 14. The amide group of formula 17 is converted to the imide of formula 19 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, trimethoxybenzyl in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VB. Alternatively, treatment of the deprotected thiol derived from compound 19 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula VB.
Nitro compounds of formula (V) wherein R14, Re, Rf, and p are defined as in this specification and a nitrate containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 15. The amide group of the formula 17 is converted to the imide of the formula 20 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred halides are bromide and iodide. Reaction of the imide of the formula 20 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VC.
Another embodiment of this aspect provides processes for making compounds having structures VI and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (VI) wherein R15, R16, Re, Rf, and p are defined as in this specification and a nitrite containing acyl imidazolide is representative of the R17 group as defined in this specification may be prepared as outlined in FIG. 16. The 1H-purine-2, 6dione of formula 21 is converted to the acylated derivative of the formula 22 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of acylated 1H-purine-2, 6-diones are reacting the 1H-purine-2, 6-dione with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the 1H-purine-2, 6-dione and protected alcohol containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIA.
Nitroso compounds of formula (VI) wherein Rl5, R16, Re, Rf, and p are defined as in this specification and a nitrosothiol containing acyl imidazolide is representative of the R17 group as defined in this specification may be prepared as outlined in FIG. 17. The 1H-purine-2, 6-dione of formula 21 is converted to the acylated derivative of the formula 23 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of acylated 1H-purine-2, 6-diones are reacting the 1H-purine-2, 6-dione, with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the 1H-purine-2, 6-dione and protected thiol containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, trimethoxybenzyl in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIB. Alternatively, treatment of the deprotected thiol derived from compound 23 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula VIB.
Nitro compounds of formula (VI) wherein R15, R16, Re, Rf, and p are defined as in this specification and an O-nitrosated acylated 1H-purine-2, 6-dione is representative of the R17 group as defined in this specification may be prepared as outlined in FIG. 18. The 1H-purine-2, 6-dione of the formula 21 is converted to the acylated derivative of the formula 24 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of acylated 1H-purine-2, 6-diones are reacting the 1H-purine-2, 6-dione with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the 1H-purine-2, 6-dione and halide containing acid in the presence of a dehydrating agent such as DCC or EDAC. HCl with a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the acylated 1H-purine-2, 6-dione of the formula 24 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VIC.
Another embodiment of this aspect provides processes for making compounds having structures VII and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (VII) wherein R8, R18, Re, Rf, and p are defined as in this specification and a nitrite containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 19. The amide nitrogen of formula 25 is converted to the imide of formula 26 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIIA.
Nitroso compounds of formula (VII) wherein R8, R18, Re, Rf, and p are defined as in this specification and a nitrosothiol containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 20. The amide nitrogen of formula 25 is converted to the imide of formula 27 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VUB. Alternatively, treatment of the deprotected thiol derived from compound 27 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula VIIB.
Nitro compounds of formula (VII) wherein R8, R18, Re, Rf, and p are defined as in this specification and a nitrate containing imide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 21. The amide group of the formula 25 is converted to the imide of the formula 28 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred halides are bromide and iodide. Reaction of the imide of the formula 28 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VIIC.
Another embodiment of this aspect provides processes for making compounds having structures VIII and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (VIII) wherein Re, Rf, and p are defined as in this specification and a nitrite containing imide is representative of the R19 group as defined in this specification may be prepared as outlined in FIG. 22 . The amide nitrogen of formula 29 is converted to the imide of formula 30 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIIIA.
Nitroso compounds of formula (VIII) wherein Re, Rf, and p are defined as in this specification and a nitrosothiol containing imide is representative of the R19 group as defined in this specification may be prepared as outlined in FIG. 23. The amide nitrogen of formula 29 is converted to the imide of formula 31 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric., acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIIB. Alternatively, treatment of the deprotected thiol derived from compound 31 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula VIIB.
Nitro compounds of formula (VIII) wherein Re, Rf, and p are defined as in this specification and a nitrate containing imide is representative of the R19 group as defined in this specification may be prepared as outlined in FIG. 24. The amide group of the formula 29 is converted to the imide of the formula 32 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of imides are reacting the amide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred halides are bromide and iodide. Reaction of the imide of the formula 32 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula VIIIC.
Another embodiment of this aspect provides processes for making compounds having structures IX and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (IX) wherein R20, Re, Rf, and p are defined as in this specification and an nitrate containing imide or sulfonimide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 25. The amide or sulfonamide nitrogen of formula 33 is converted to the imide or sulfonimide of formula 34 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of imides or sulfonimide are reacting the amide or sulfonimide with the preformed acid chloride of the protected alcohol containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonimide and protected alcohol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IXA
Nitroso compounds of formula (IX) wherein R20, Re, Rf, and p are defined as in this specification and an nitrosothiol containing imide or sulfonimide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 26. The amide or sulfonamide nitrogen of formula 33 is converted to the imnide or sulfonimide of formula 35 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2is as defined in this specification. Preferred methods for the formation of imides or sulfonimides are reacting the amide or sulfonimide with the preformed acid chloride of the protected thiol containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonimide and protected thiol containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IXB. Alternatively, treatment of the deprotected thiol derived from compound 35 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or alcoholic solution affords the compound of the formula IXB.
Nitro compounds of formula (IX) wherein R20, Re, Rf, and p are defined as in this specification and a nitrate containing imide or sulfonimide is representative of the R4 group as defined in this specification may be prepared as outlined in FIG. 27. The amide or sulfonamide group of the formula 33 is converted to the imide or sulfonimide of the formula 36 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of imides or sulfonimide are reacting the amide or sulfonamide with the preformed acid chloride of the halide containing acid in the presence of pyridine at low temperature or condensing the amide or sulfonamide and halide containing symmetrical anhydride in the presence of a catalyst such as sulfuric acid. Preferred halides are bromide and iodide. Reaction of the imide or sulfonimide of the formula 36 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula IXC.
Another embodiment of this aspect provides processes for making compounds having structures X and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (X) wherein D1, Re, Rf, and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 28. The alcohol group of formula 37 is converted to the ester of formula 38 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the alcohol and protected alcohol containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, TIF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XA.
Nitroso compounds of formula (X) wherein D1, Re, Rf, and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 29. The alcohol group of the formula 37 is converted to the ester of the formula 39 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the alcohol and protected thiol containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBT. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XB. Alternatively, treatment of the deprotected thiol derived from compound 39 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic acid affords the compound of the formula XB.
Nitro compounds of formula (X) wherein D1, Re, Rf, and p are defined as in this specification and a nitrate containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 30. The alcohol group of the formula 37 is converted to the ester of the formula 40 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an approriate halide containing activated acylating agent Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt Preferred halides are bromide and iodide. Reaction of the ester of the formula 40 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XC.
Nitroso compounds of formula (XI) wherein D1, Re, Rf, and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 31. The alcohol group of formula 41 is converted to the ester of formula 42 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing activated acylating agent wherein P1 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid or condensing the alcohol and protected alcohol containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIA.
Nitroso compounds of formula (XI) wherein D1, Re, Rf, and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 32. The alcohol group of the formula 41 is converted to the ester of the formula 43 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing activated acylating agent wherein P2 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid or condensing the alcohol and protected thiol containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a disulfide, a thioester such as a thioacetate or thiobenzoate, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylmethyl in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIB. Alternatively, treatment of the deprotected thiol derived from compound 43 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic acid affords the compound of the formula XIB.
Nitro compounds of formula (XI) wherein D1, Re, Rf, and p are defined as in this specification and a nitrate containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 33. The alcohol group of the formula 41 is converted to the ester of the formula 44 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing activated acylating agent. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the ester of the formula 44 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XIC.
Another embodiment of this aspect provides processes for making compounds having structures XII and to the intermediates useful in such processes as follows.
Nitroso compounds of formula (XI) wherein Re, Rf, R23, R24, R25, J, V and p are defined as in this specification and a nitrite containing thioester is representative of the K-T-D group as defined in this specification may be prepared according to Scheme 34. The carboxylic acid group of formula 45 is converted to the thioester of formula 46 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing thiol agent wherein P1 is as defined in this specification. Preferred methods for the formation of thioesters are reacting the thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIIA.
Nitroso compounds of formula (XII) wherein Re, Rf, R23, R24, R25, J, V and p are defined as in this specification and a nitrosothiol containing thioester is representative of the K-T-D group as defined in this specification may be prepared according to Scheme 35. The carboxylic acid group of formula 45 is converted to the thioester of formula 47 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate mono protected dithiol. Preferred methods for the formation of thioesters are reacting the free thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the free thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a disulfide, a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylmethyl in water and sodium borohydride are preferred methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group). Reaction of the free thiol with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIIB. Alternatively, treatment of the thiol in compound 47 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic acid affords the compound of the formula XIIB.
Nitro compounds of formula (XII) wherein Re, Rf, R23, R24, R25, J, V and p are defined as in this specification and a nitrate containing thioester is representative of the K-T-D group as defined in this specification may be prepared according to Scheme 36. The carboxylic acid group of formula 45 is converted to the thioester of formula 46 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected alcohol containing thiol agent wherein P1 is as defined in this specification. Preferred methods for the formation of thioesters are reacting the thiol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction of the alcohol with a suitable nitrating agent such as nitric acid and acetic anhydride in ethyl acetate/acetic acid affords the compound of the formula XIIC.
Nitroso compounds of formula () wherein Re, Rf, R31, R32, and p are defined as in this specification and a nitrite containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 37. The carboxylic acid group of formula 48 is converted to the ester of formula 49 wherein p, Re and Rf are defined as in this specification by reaction with an monoprotected protected diol wherein P1 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the alcohol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIIIA.
Nitroso compounds of formula (XIII) wherein Re, Rf, R31, R32, and p are defined as in this specification and a nitrosothiol containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 38. The carboxylic acid group of formula 48 is converted to the ester of formula 50 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate protected thiol containing alcohol. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the primary thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as a disulfide, a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group). Reaction of the free thiol with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula XIIIB. Alternatively, treatment of the thiol in compound 50 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic acid affords the compound of the formula XIIIB.
Nitro compounds of formula (XIII) wherein Re, Rf, R31, R32, and p are defined as in this specification and a nitrate containing ester is representative of the D group as defined in this specification may be prepared according to Scheme 39. The carboxylic acid group of formula 48 is converted to the ester of formula 49 wherein p, Re and Rf are defined as in this specification by reaction with an appropriate monoprotected protected diol wherein p1 is as defined in this specification. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the carboxylic acid or condensing the alcohol and carboxylic acid with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction of the alcohol with a suitable nitrating agent such as nitric acid and acetic anhydride in ethyl acetate/acetic acid affords the compound of the formula XIIIC. Alternatively, carboxylic acid group of the formula 48 is converted to the ester of the formula 51 wherein p, Re and Rf are defined as in this specification and X is a halogen by reaction with an appropriate halide containing alcohol. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the halide containing acid or condensing the alcohol and halide containing alcohol with a dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the ester of the formula 51 with a suitable nitrating agent such as silver nitrate in an inert solvent such as acetonitrile affords the compound of the formula XIIIC.
As noted above, another aspect the invention provides a composition comprising (i) a therapeutically effective amount of a PDE inhibitor, which optionally can be substituted with at least one NO or NO2 group or a group that stimulates endogenous production of NO or EDRF in vivo, and (ii) a compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NO.) and/or a compound that stimulates endogenous production of NO or EDRF in vivo.
The compounds that donate, transfer or release nitric oxide can be any of those known to the art, including those mentioned and/or exemplified below.
Nitrogen monoxide can exist in three forms: NOxe2x88x92 (nitroxyl), NO. (nitric oxide) and NO+ (nitrosonium). NO. is a highly reactive short-lived species that is potentially toxic to cells. This is critical, because the pharmacological efficacy of NO depends upon the form in which it is delivered. In contrast to NO., nitrosonium and nitroxyl do not react with O2 or O2xe2x88x92 species. Consequently, administration of NO equivalents does not result in the generation of toxic by-products or the elimination of the active NO moiety.
Compounds contemplated for use in the invention are nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo. As used here, the term xe2x80x9cnitric oxidexe2x80x9d encompasses uncharged nitric oxide (NO.) and charged nitric oxide species, particularly including nitrosonium ion (NO+) and nitroxyl ion (NOxe2x88x92). The reaction form of nitric oxide can be provided by gaseous nitric oxide. The nitric oxide releasing, delivering or transferring compounds, having the structure Fxe2x80x94NO wherein F is a nitric oxide releasing, delivering or transferring moiety, include any and all such compounds which provide nitric oxide to its intended site of action in a form active for their intended purpose. As used here, the term xe2x80x9cNO adductsxe2x80x9d encompasses any of such nitric oxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-((E))-hydroxyimino)-5-nitro-3-hexeneamines or hexeneamides, nitrosoamines, as well as substrates for the endogenous enzymes which synthesize nitric oxide. It is contemplated that any or all of these xe2x80x9cNO adductsxe2x80x9d can be mono- or poly-nitrosylated or nitrosated at a variety of naturally susceptible or artificially provided binding sites for nitric oxide or derivatives which donate or release NO.
One group of such NO adducts is the S-nitrosothiols, which are compounds that include at least one xe2x80x94Sxe2x80x94NO group. Such compounds include S-nitroso-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars, S-nitrosylated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and an S-nitrosylated hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; S-nitrosylated hydrocarbons having one or more substituent groups in addition to the S-nitroso group; and heterocyclic compounds. S-nitrosothiols and the methods for preparing them are described in U.S. Pat. No. 5,380,758; Oae et al., Org. Prep. Proc. Int., 15(3):165-198 (1983); Loscalzo et al., J. Pharmacol. Exp. Ther., 249(3):726729 (1989) and Kowaluk et al., J. Pharmacol. Exp. Ther., 256:1256-1264 (1990), all of which are incorporated in their entirety by reference.
One particularly preferred embodiment of this aspect relates to S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof. For example, such compounds include the following: S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.
Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur group on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin; and biologically protective proteins, such as the immunoglobulins and the cytokines. Such nitrosylated proteins are described in PCT Publ. Applic. No. WO 93/09806, published May 27, 1993. Examples include polynitrosylated albumin where multiple thiol or other nucleophilic centers in the protein are modified.
Further examples of suitable S-nitrosothiols include those having the structures:
CH3[C(Re)(Rf)]xSNOxe2x80x83xe2x80x83(i)
wherein x equals 2 to 20 and Re and Rf are as defined in this specification;
HS[C((Re)(Rf)]xSNOxe2x80x83xe2x80x83(ii)
wherein x equals 2 to 20; and Re and Rf are as defined in this specification;
ONS[C(Re)(Rf)]xB;xe2x80x83xe2x80x83(iii)
and
H2Nxe2x80x94CH(CO2H)xe2x80x94(CH2)xxe2x80x94C(O)NHxe2x80x94C(CH2SNO)xe2x80x94C(O)NHxe2x80x94CH2xe2x80x94CO2Hxe2x80x83xe2x80x83(iv)
wherein x equals 2 to 20; Re and Rf are as defined in this specification; and B is selected from the group consisting of fluoro, C1-C6 alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylno, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl.
Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared fist, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO2 under acidic conditions (pH is about 2.5) to yield the S-nitroso derivative. Acids which may be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids. Alternatively, the precursor thiol may be nitrosylated by treatment with an alkyl nitrite such as tert-butyl nitrite.
Another group of such NO adducts are those wherein the compounds donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one ONxe2x80x94Nxe2x80x94 or ONxe2x80x94Cxe2x80x94 group. The compound that includes at least one ONxe2x80x94Nxe2x80x94 or ONxe2x80x94Cxe2x80x94 group is preferably selected from the group consisting of ONxe2x80x94Nxe2x80x94or ONxe2x80x94C-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-amino acids(including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-sugars; ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides), ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-hydrocarbons which can be branched or unbranched, saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons; ONxe2x80x94Nxe2x80x94 or ONxe2x80x94Cxe2x80x94 hydrocarbons having one or more substituent groups in addition to the ONxe2x80x94Nxe2x80x94 or ONxe2x80x94Cxe2x80x94 group; and ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-heterocyclic compounds.
Another group of such NO adducts is the nitrites which have an xe2x80x94Oxe2x80x94NO group wherein the organic template to which the nitrite group is appended is a protein, polypeptide, amino acid, carbohydrate, branched or unbranched and saturated or unsaturated alkyl, aryl or a heterocyclic compound. A preferred example is the nitrosylated form of isosorbide. Compounds in this group form S-nitrosothiol intermediates in vivo in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor Rxe2x80x94Oxe2x80x94NO of the S-nitrosothiols described above.
Another group of such adducts are nitrates which donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one at least one O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 group. Preferred among these are those selected from the group consisting of O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-polypeptides; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-amino acids; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 sugars; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-modified and unmodified oligonucleotides; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 hydrocarbons which can be branched or unbranched, saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 hydrocarbons having one or more substituent groups in addition to the O2Nxe2x80x94O, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 group; and O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94Cxe2x80x94 heterocyclic compounds. Preferred examples are isosorbide dinitrate and isosorbide mononitrate.
Another group of such NO adducts is the nitroso-metal compounds which have the structure (R)uxe2x80x94Axe2x80x94M(NO)v. R includes polypeptides (the termn xe2x80x9cpolypeptidexe2x80x9d includes proteins and also polyamino acids that do not posses an ascertained biological function, and derivatives thereof); amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; hydrocarbons having one or more substituent groups in addition to the A-nitroso group; and heterocyclic compounds. A is S, O, or N, u and v are each integers independently selected from 1, 2 and 3, and M is a metal, preferably a transition metal. Preferred metals include iron, copper, manganese, cobalt, selenium and luthidium. Also contemplated are N-nitrosylated metal centers such as nitroprusside.
Another group of such adducts are 2-hydroxy-2-nitrosohydrazines which donate, transfer or release nitric oxide and have a R61R62xe2x80x94N(Oxe2x80x94M+)xe2x80x94NO group wherein R61 and R62 include polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or an aromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds. M+ is a metal cation, such as, for example, a Group I metal cation.
Another group of such adducts are thionitrates which donate, transfer or release nitric oxide and have the structure R61xe2x80x94Sxe2x80x94NO2 wherein R61 is as described above.
Compounds that stimulate endogenous synthesis of NO or EDRF in vivo include L-arginine, the substrate for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, and endothelin.
When administered in vivo, the nitric oxide may be administered in combination with pharmaceutical carriers and in dosages described herein.
The nitrosated or nitrosylated compounds of the invention are used at dose ranges and over a course of dose regimen and are administered in the same or substantially equivalent vehicles/carrier by the same or substantially equivalent oral or nasal inhalant devices as their non-nitrosated or non-nitrosylated counterparts. The nitrosated or nitrosylated compounds of the invention can also be used in lower doses and in less extensive regimens of treatment. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about 1 to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state targeted for treatment. The compositions of the invention can also be administered as described above or can be made to include one or more additional active compounds which are known to be effective against the specific disease state is targeted for treatment.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
These and other aspects of the present invention will be apparent to those skilled in the art from the teachings herein.